The use of antiepileptic or anesthetic drugs during gestation and infancy is one of the thorniest issues in clinical neurology and neonatology. This is because the developing brain is exquisitely sensitive to drug-induced perturbations of the chemical environment of neurons. Therefore, increasing attention is being devoted to identifying therapeutic strategies to avoid/minimize adverse developmental outcomes while maximizing clinical benefits to neonates and pregnant women.
The scope of this clinical problem is great: over half a million women of childbearing age are treated for epilepsy in the United States alone. Moreover, antiepileptic drugs and anesthesia are interventions frequently required for the medical treatment of neonates. The problem is even greater in developing countries where older, more toxic drugs are in widespread use.
Clinically, exposure to these agents during brain maturation has been associated with alterations in cognitive performance later in life. The possibility that pre- or post-natal exposure to these drugs may be a risk factor for neuropsychiatric outcomes (such as autism and schizophrenia) has been suggested. Preclinical evidence showing induction of neuronal apoptosis following brief exposure to antiepileptic and anesthetic drugs in immature animals has raised concerns about potential long-term neurotoxicity, as have animal models in which developmental drug exposure results in adverse behavioral outcomes. The extent to which the preclinical findings translate to the human is a pressing topic of discussion.
To integrate the basic and clinical findings, several questions must be answered:
How does the time course of brain development in experimental animals map onto brain development in humans? What neurological and psychiatric abnormalities occur following developmental exposure to the drugs? How does prenatal drug exposure compare with neonatal drug exposure? What are the sensitive periods for toxicity to various drugs? Can research on fetal alcohol spectrum disorders help to inform studies on antiepileptic and anesthetic drugs? What are the mechanisms by which early life drug exposure alters nervous system function in adulthood?
Through molecular, genetic, histopathological, electrophysiological and behavioral assessment of animal models, and through analysis of clinical outcomes in humans, we intend to highlight the current state of knowledge and key targets for future research. A special emphasis will be placed on novel therapeutic paradigms to minimize, avoid, or ameliorate the deleterious effects of antiepileptic drugs and anesthetics on the developing brain, while maximizing clinical benefit.
The use of antiepileptic or anesthetic drugs during gestation and infancy is one of the thorniest issues in clinical neurology and neonatology. This is because the developing brain is exquisitely sensitive to drug-induced perturbations of the chemical environment of neurons. Therefore, increasing attention is being devoted to identifying therapeutic strategies to avoid/minimize adverse developmental outcomes while maximizing clinical benefits to neonates and pregnant women.
The scope of this clinical problem is great: over half a million women of childbearing age are treated for epilepsy in the United States alone. Moreover, antiepileptic drugs and anesthesia are interventions frequently required for the medical treatment of neonates. The problem is even greater in developing countries where older, more toxic drugs are in widespread use.
Clinically, exposure to these agents during brain maturation has been associated with alterations in cognitive performance later in life. The possibility that pre- or post-natal exposure to these drugs may be a risk factor for neuropsychiatric outcomes (such as autism and schizophrenia) has been suggested. Preclinical evidence showing induction of neuronal apoptosis following brief exposure to antiepileptic and anesthetic drugs in immature animals has raised concerns about potential long-term neurotoxicity, as have animal models in which developmental drug exposure results in adverse behavioral outcomes. The extent to which the preclinical findings translate to the human is a pressing topic of discussion.
To integrate the basic and clinical findings, several questions must be answered:
How does the time course of brain development in experimental animals map onto brain development in humans? What neurological and psychiatric abnormalities occur following developmental exposure to the drugs? How does prenatal drug exposure compare with neonatal drug exposure? What are the sensitive periods for toxicity to various drugs? Can research on fetal alcohol spectrum disorders help to inform studies on antiepileptic and anesthetic drugs? What are the mechanisms by which early life drug exposure alters nervous system function in adulthood?
Through molecular, genetic, histopathological, electrophysiological and behavioral assessment of animal models, and through analysis of clinical outcomes in humans, we intend to highlight the current state of knowledge and key targets for future research. A special emphasis will be placed on novel therapeutic paradigms to minimize, avoid, or ameliorate the deleterious effects of antiepileptic drugs and anesthetics on the developing brain, while maximizing clinical benefit.
